PRODUCT MONOGRAPH. vemurafenib. Film-coated tablet, 240 mg. Professed Standard. Protein Kinase Inhibitor

Transcription

1 PRODUCT MONOGRAPH Pr ZELBORAF vemurafenib Film-coated tablet, 240 mg Professed Standard Protein Kinase Inhibitor Hoffmann-La Roche Limited 7070 Mississauga Road Mississauga, Ontario, Canada L5N 5M8 Date of Revision: February 15, Submission Control No: ZELBORAF is a registered trade-mark of F. Hoffmann-La Roche AG, used under license. Manufactured under license from Plexxikon Inc., a member of the Daiichi Sankyo group. Copyright , Hoffmann-La Roche Limited Page 1 of 43

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION...3 SUMMARY PRODUCT INFORMATION...3 INDICATIONS AND CLINICAL USE...3 CONTRAINDICATIONS...4 WARNINGS AND PRECAUTIONS...4 ADVERSE REACTIONS...11 DRUG INTERACTIONS...19 DOSAGE AND ADMINISTRATION...22 OVERDOSAGE...25 ACTION AND CLINICAL PHARMACOLOGY...25 STORAGE AND STABILITY...27 SPECIAL HANDLING INSTRUCTIONS...27 DOSAGE FORMS, COMPOSITION AND PACKAGING...27 PART II: SCIENTIFIC INFORMATION...28 PHARMACEUTICAL INFORMATION...28 CLINICAL TRIALS...29 DETAILED PHARMACOLOGY...35 TOXICOLOGY...36 REFERENCES...38 PART III: CONSUMER INFORMATION...39 Page 2 of 43

3 Pr ZELBORAF vemurafenib PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form / Administration Strength oral Film-coated tablet / 240 mg Clinically Relevant Non-medicinal Ingredients No clinically relevant non-medicinal ingredients. For a complete listing see Dosage Forms, Composition and Packaging section. INDICATIONS AND CLINICAL USE ZELBORAF (vemurafenib) is indicated as a monotherapy for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma. A validated test is required to identify BRAF V600 mutation status. BRAF V600 mutations were identified in the Phase III and Phase II studies by the Health Canada approved cobas 4800 BRAF V600 Mutation Test. Clinical data supporting the effectiveness of ZELBORAF in patients with BRAF mutations other than V600E are limited. ZELBORAF should not be used in patients with BRAF wild-type melanoma (see WARNINGS and PRECAUTIONS, General). ZELBORAF has not been studied in patients previously treated with BRAF inhibitors. ZELBORAF should be prescribed and supervised by a qualified physician experienced in the use of anti-cancer agents. Geriatrics ( 65 years of age): In clinical studies, elderly patients ( 65 years) experienced more adverse events when taking ZELBORAF (see WARNINGS AND PRECAUTIONS, Special Populations). Pediatrics (< 18 years of age): Page 3 of 43

4 The safety and efficacy of ZELBORAF in patients under the age of 18 have not been established. Vemurafenib is not approved for use in patients under the age of 18 years. CONTRAINDICATIONS ZELBORAF (vemurafenib) is contraindicated in Patients who are hypersensitive to ZELBORAF or to any ingredient in the formulation. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Serious adverse reactions and/or life threatening events include: Liver injury. QTc interval prolongation (see Cardiovascular below). Second malignancies (see Malignancies below). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) (see Immune below). Radiation sensitization and radiation recall (see Radiation Sensitization and Radiation Recall below). ZELBORAF has not been studied in patients with severe hepatic impairment (see Special Populations/Hepatic Impairment below). ZELBORAF (vemurafenib) tablets should be prescribed and supervised by a qualified physician experienced in the use of anti-cancer agents. General A validated test is required to detect BRAF V600 mutation-positive tumours in patients treated with ZELBORAF (vemurafenib). In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in BRAF wild-type cells exposed to BRAF inhibitors. This may promote growth of wild-type BRAF melanomas. New primary melanomas have been reported in patients taking ZELBORAF (see Malignancies below). ZELBORAF should not be used in patients with wild-type BRAF tumours or in patients where the BRAF mutational status is not known. The cobas BRAF 4800 Mutation Test was designed for and has a high sensitivity to detect V600E mutations in tumours (80-90% of all BRAF mutations in melanomas). It has reduced sensitivity for detecting less common BRAF V600 mutations including V600K, the second most Page 4 of 43

5 common BRAF mutation in melanomas (see Part II, CLINICAL TRIALS). Clinical data supporting use of ZELBORAF in patients with BRAF mutations other than V600E are limited. Tumour Lysis Syndrome (TLS) One case of vemurafenib treatment-related TLS occurred in the Phase II study of 132 previously treated melanoma patients. Malignancies Cutaneous Squamous Cell Carcinoma (cuscc) Cases of cuscc (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with ZELBORAF (see ADVERSE REACTIONS). The incidence of cuscc in patients treated with ZELBORAF across all studies was approximately 27%. The majority of excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixedkeratoacanthoma features (52%). Most lesions classified as other (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, cyst/benign cyst). CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuscc, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuscc in ZELBORAF clinical trials included age ( 65 years), prior skin cancer, RAS mutations, and chronic sun exposure. Cases of cuscc were typically managed with simple excision, and patients were able to continue treatment without dose adjustment. Nonclinical studies demonstrated that administration of vemurafenib to mice increased the proliferation of human cusccs in a xenograft tumour model of the disease (see DETAILED PHARMACOLOGY, Secondary Pharmacodynamics). It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per local standard of care. No dose adjustment is required. Monitoring should continue for 6 months following discontinuation of ZELBORAF. Patients should be instructed to inform their physicians of the occurrence of any skin changes. New Primary Melanoma In the Phase III clinical study, 7 patients (2.0%) experienced new primary melanomas. Manage with excision and continue treatment without dose modification. Perform dermatologic monitoring as above for cutaneous squamous cell carcinoma. Non-Cutaneous Malignancies The paradoxical activation of MAP-kinase signaling in BRAF wild type cells exposed to BRAF inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations, in patients taking ZELBORAF. In clinical studies cases of squamous cell carcinomas of the head and neck (tongue and tonsils) have been reported in association with ZELBORAF. In the post-market setting, progression of a pre-existing pancreatic adenocarcinoma in one patient Page 5 of 43

6 and chronic myelomonocytic leukemia (CMML) in a second patient have occurred during treatment with ZELBORAF. The CMML possessed a RAS mutation (see ADVERSE REACTIONS) and KRAS mutations are frequently found in pancreatic cancer. Vemurafenib should be used with caution in patients with a prior or concurrent cancer, particularly those associated with RAS mutations. Patients should undergo head and neck examination consisting of at least a visual inspection of oral mucosa and lymph node palpation, prior to initiation of treatment and every 3 months during treatment. Pelvic (for women) and anal examinations should also be done prior to initiation of treatment, at the end of treatment, or when considered clinically indicated. In addition, patients should undergo a chest CT scan prior to initiation of treatment and every 6 months during treatment. Following discontinuation of ZELBORAF, monitoring for non-cutaneous malignancies should continue for up to 6 months. Abnormal findings should be evaluated as clinically indicated. Cardiovascular QT Prolongation In both Phase II and Phase III studies, patients were excluded if they had a baseline QTc interval of 450 msec. Exposure-dependent QTc prolongation was observed in an uncontrolled, open-label Phase II QT sub-study in previously treated patients with metastatic melanoma. Analysis of centralized ECG data from this study in 132 patients treated with ZELBORAF 960 mg twice daily showed a mean increase from baseline in QTc at Day 1 (3.3 ms; upper 95% CI: 5 ms) and Day 15 (12.8 ms; upper 95% CI: 14.9 ms). The mean QTc effect remained stable between 12 and 15 ms beyond the first month of treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed at the Cycle 6 (week 18) assessment (n=85 patients). Maximum treatmentemergent individual QTc changes from baseline of > 30 ms were observed in 58 patients (45%). Two patients (1.6%) developed treatment-emergent absolute QTc values > 500 ms (CTCAE Grade 3), and one patient (0.8%) exhibited a QTc change from baseline of >60 ms. QTc prolongation with ZELBORAF showed a positive concentration-response relationship. QTc prolongation was also observed in the Phase III clinical trial in previously untreated patients with unresectable stage IIIC or stage IV melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), long QT syndrome, or who are taking medicinal products known to prolong the QT interval (DRUG INTRERACTIONS, Overview). Caution should be exercised when administering ZELBORAF to patients who have other risk factors for torsade de pointes such as age 65 years or older, family history of sudden cardiac death at <50 years, cardiac disease, history of arrhythmias, bradycardia, acute neurological events, diabetes mellitus and autonomic neuropathy. Page 6 of 43

7 ECG and electrolytes should be monitored before treatment with ZELBORAF and after dose modification. Further monitoring should occur at day 15 and monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If, during treatment, the QTc exceeds 500 ms (CTCAE grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) should be controlled. Reinitiation of treatment should not occur until the QTc decreases below 500 ms and should be reinitiated at a lower dose, as described in Table 6 and Table 7 (see DOSAGE AND ADMINISTRATION: Recommended Dose and Dosage Adjustment). Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc meets values of both > 500 ms and > 60 ms increase from pre-treatment values and if recommended dose reductions are not effective to manage when the QTc meets values of > 500 ms but 60 ms increase from pre-treatment values (Table 7). Hypertension Elevations in blood pressure have been reported in association with ZELBORAF. The mean change from baseline ranged from 4-10 mmhg for Systolic Blood Pressure (SBP) and 0-8 mmhg for Diastolic Blood Pressure (DBP) over the course of treatment. Mean absolute blood pressure remained less than <140/90 mmhg. Hypertension was reported as an adverse event in 3% of patients treated with ZELBORAF (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions). Blood pressure should be monitored during ZELBORAF treatment, with control of hypertension as appropriate (See Monitoring and Laboratory Tests). Patients were excluded from clinical studies if they had uncontrolled hypertension. Hepatic Liver injury, including cases reported as hepatic failure have occurred in the post-market setting with ZELBORAF monotherapy. Elevations in transaminases (ALT/AST), alkaline phosphatase and bilirubin have also been reported with ZELBORAF monotherapy in the Phase III study (see Monitoring and Laboratory Tests and ADVERSE REACTIONS - Post-Market Adverse Drug Reactions). Concurrent Administration with Ipilimumab In a Phase I trial, grade 3 increases in transaminases and bilirubin were reported in a majority of patients who received concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Given these liver toxic effects, the (combination) study was closed to further patient accrual. The concurrent administration of ipilimumab and vemurafenib is not recommended. Immune Serious hypersensitivity reactions, including anaphylaxis have been reported in association with ZELBORAF (see CONTRAINDICATIONS and ADVERSE REACTIONS). A case of hypersensitivity reaction with rash, fever, rigors and hypotension 8 days after starting ZELBORAF 960 mg twice daily was reported in a clinical trial. Similar symptoms were Page 7 of 43

8 observed upon re-initiation of treatment with a single dose of 240 mg ZELBORAF. The patient discontinued ZELBORAF permanently and recovered without sequelae. Severe hypersensitivity reactions included generalized rash, erythema, and hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. Severe dermatologic reactions have occurred in association with ZELBORAF. There have been cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a potentially life threatening syndrome including severe skin eruption, lymphadenopathy, fever, hematological abnormalities (eosinophilia or atypical lymphocytes) and internal organ involvement, reported in the post-market setting. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported in the pivotal clinical trial as uncommon events, and in the postmarket setting. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. Musculoskeletal and connective tissue disorders Dupuytren s contracture and plantar fascial fibromatosis Dupuytren s contracture and plantar fascial fibromatosis have been reported with vemurafenib. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren s contracture have also been reported (see ADVERSE REACTIONS - Clinical Trial Adverse Drug Reactions, ADVERSE REACTIONS - Post-Market Adverse Drug Reactions). Events should be managed with dose reduction, treatment interruption, or with treatment discontinuation (see DOSAGE AND ADMINISTRATION - Dose Adjustment). Ophthalmologic ZELBORAF treatment-related serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have been reported (see ADVERSE REACTIONS). Monitor patients routinely for ophthalmologic reactions. Pancreatitis Cases of drug-induced pancreatitis have been reported in clinical studies and in the postmarketing setting, generally occurring within two weeks after initiation of ZELBORAF treatment. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase in addition to other appropriate diagnostic work up (e.g. CT abdomen). Patients should be closely monitored if re-starting vemurafenib after an episode of pancreatitis, and dose modification should be considered. Renal Acute kidney injury ranging from mild to moderate elevations of serum creatinine levels to acute interstitial nephritis and acute tubular necrosis was reported with ZELBORAF treatment in clinical trials and in the post-market setting. In a phase III clinical study, elevations of serum creatinine were mild (> x ULN) to moderate (> x ULN) and appeared to be reversible in nature in most cases. The incidence of serum creatinine elevations was 40% in Page 8 of 43

9 patients treated with ZELBORAF (compared to 6% for patients treated with dacarbazine). Acute kidney injury was reported in 10% of patients in the ZELBORAF arm (compared to 1.4% in the control arm), see ADVERSE REACTIONS. Serum creatinine should be measured before initiation of treatment with ZELBORAF and periodically monitored during ZELBORAF treatment as clinically indicated. For recommended dose modifications, see DOSAGE AND ADMINISTRATION, Dose Adjustment. Skin Photosensitivity Mild to severe photosensitivity was reported in patients who were treated with ZELBORAF in clinical trials (see ADVERSE REACTIONS). All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sun screen and lip balm (SPF 30) when outdoors to help protect against sunburn. For photosensitivity, grade 2 (intolerable) or greater adverse events, dose modifications are recommended (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment). Radiation Sensitization and Radiation Recall Cases of radiation sensitization and radiation recall have been reported in patients treated with radiation prior to, during, or following ZELBORAF treatment in the post-marketing setting. Most cases were cutaneous in nature but some cases involving visceral organs had fatal outcomes (see Post-Market Adverse Drug Reactions and DRUG INTERACTIONS, Radiation Sensitization and Radiation Recall). The cases of radiation recall showed acute inflammation confined to previously irradiated area, triggered by ZELBORAF administration 7 or more days after completion or radiotherapy. The majority of cases affected the skin while the remaining cases involved the lung and urinary bladder. The cases of radiation sensitization showed potentiation of radiation reaction evidenced by the greater than expected severity of the reaction for local radiation injury. The majority of cases involved the skin, while other cases involved the oesophagus, liver, brain and rectum. In nearly all cases, patients were either dosed concomitantly with radiation or within 3 days after completion of radiotherapy. One case was a patient with metastatic liver disease who developed radiation necrosis of the liver 10 weeks after receiving 20 Gy over 5 fractions radiation over the thoracic spine while ZELBORAF treatment was temporarily withheld. Two patients experienced radiation necrosis of the brain while receiving ZELBORAF. It is recommended that ZELBORAF not be used concomitantly with radiation therapy, unless the potential benefit justifies the potential risk to the patient. Page 9 of 43

10 Special Populations Fertility: No preclinical fertility studies have been conducted. No histopathological findings were noted in reproductive organs in males and females in repeat-dose toxicology studies ( see TOXICOLOGY) Pregnant Women: ZELBORAF crosses the placenta in rats (fetuses have 3-5% of maternal levels) and may cause fetal harm by interfering with BRAF function, which is essential for the developing embryo.zelboraf was not teratogenic in rat or rabbit embryo/fetuses when animals were exposed at 1.7X and 0.7X human exposure levels, respectively (see TOXICOLOGY). ZELBORAF should not be administered to pregnant women unless the possible benefits for the mother outweigh the possible risk to the fetus. There are no adequate or well-controlled studies in pregnant women however, placental transfer of vemurafenib to a fetus (approximately 50% of maternal levels) has been reported. Based on its mechanism of action, vemurafenib could cause fetal harm when administered to a pregnant woman. Women of childbearing potential and men are recommended to use appropriate contraceptive measures during treatment with ZELBORAF and for at least 6 months after discontinuation of ZELBORAF. Labor and Delivery: The safe use of ZELBORAF during labor and delivery has not been established. Nursing Women: It is not known whether ZELBORAF is excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or discontinue treatment with ZELBORAF after considering the benefits of breast feeding for the child and the benefits of therapy for the mother. Pediatrics: The safety and efficacy of ZELBORAF in patients below 18 years of age have not been established. Vemurafenib is not approved for use in patients under the age of 18 years. Geriatrics: Ninety-four of 336 patients (28%) with unresectable or metastatic melanoma treated with ZELBORAF in the Phase III study were 65 years. In clinical studies, elderly patients ( 65 years) experienced more adverse events, including cuscc, decreased appetite, and cardiac disorders. The effects of ZELBORAF on overall survival, progression-free survival and best overall response rate were similar in the elderly and younger patients. Gender: Page 10 of 43

11 The grade 3 adverse events reported more frequently in females than males were rash, arthralgia and photosensitivity (see ADVERSE REACTIONS and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions). Renal Impairment: The safety and efficacy of ZELBORAF have not been studied in patients with renal impairment. Hepatic Impairment: ZELBORAF has not been studied in patients with severe hepatic impairment. Since ZELBORAF is primarily eliminated by the liver, patients with severe hepatic impairment may have higher systemic concentrations that could result in more frequent and/or severe exposure-related adverse events including QTc prolongation (see DOSAGE AND ADMINISTRATION: Dose Adjustment/Hepatic Impairment). Monitoring and Laboratory Tests Before taking ZELBORAF, patients should have BRAF V600 mutation-positive tumour status confirmed by an experienced laboratory using a validated test. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be measured before initiation of treatment and monitored monthly during treatment, or as clinically indicated, as hepatotoxicity may occur with ZELBORAF. For recommended dose modifications, see DOSAGE AND ADMINISTRATION, Dose Adjustment. ECG monitoring and electrolyte determinations should be performed at baseline, day 15; months 1, 2, and 3; and at 3 month intervals thereafter or more often if clinically indicated. Blood pressure monitoring and eye examinations should be performed at baseline and periodically during treatment with ZELBORAF. Creatinine: Serum creatinine should be measured before initiation of treatment and periodically monitored during treatment as clinically indicated. ADVERSE REACTIONS Adverse Drug Reaction Overview The most common adverse drug reactions (> 30%) reported in patients treated with ZELBORAF (vemurafenib) include arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, diarrhea, headache, pruritus and skin papilloma, the majority of which were mild or moderate in intensity. Clinical Trial Adverse Drug Reactions Page 11 of 43

12 Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The adverse drug reactions (ADRs) described in this section were identified from two clinical trials, a Phase III study (NO25026) in treatment-naïve patients with BRAF V600 mutationpositive unresectable or metastatic melanoma and a Phase II study (NP22657) in patients with BRAF V600 mutation-positive metastatic melanoma who have failed at least one prior systemic therapy. In the Phase III open-label study, 675 patients were randomized in a 1:1 ratio to either ZELBORAF or dacarbazine; the patients randomized to the ZELBORAF arm received a twice daily oral starting dose of 960 mg; patients randomized to the active control arm received dacarbazine 1000 mg/m 2 administered intravenously every 3 weeks. The median duration of ZELBORAF treatment for safety evaluations was 6.62 months compared to 0.79 months for dacarbazine. The Phase II study was an open-label, uncontrolled, single-arm study in which 132 patients received ZELBORAF 960 mg twice daily. The median treatment duration in this study was 5.7 months. In the Phase III study, a higher percentage of patients treated with ZELBORAF (47%) than dacarbazine (18%) experienced serious adverse events (SAEs). The most common ( 1%) Grade 3 SAEs in the patients treated with ZELBORAF were (preferred terms): squamous cell carcinoma of the skin (19%), keratoacanthoma (10%), malignant melanoma (2%), and basal cell carcinoma (1%). Dacarbazine-related SAEs were mostly infections and infestations in nature. Across all studies, a small percentage of patients experienced AEs that led to study treatment discontinuation. The incidence of adverse events resulting in permanent discontinuation of study medication in the Phase III study for patients treated with ZELBORAF was 7% and 2% for patients treated with dacarbazine. In the Phase II study, the incidence of adverse events resulting in permanent discontinuation of study medication was 3%. Table 1 summarizes the ADRs occurring in at least 10% of patients treated with ZELBORAF in either the Phase III or Phase II studies. Page 12 of 43

13 Table 1 Summary of ADRs* Occurring in 10% in Patients Treated with ZELBORAF ADRs All Grades (%) Phase III Study: Treatment Naïve Patients** Phase II Study: Patients who Failed at Least One Prior Systemic Therapy ZELBORAF Dacarbazine ZELBORAF n= n= n= 132 Grade 3 (%) Skin and subcutaneous tissue disorders Grade 4 (%) All Grades (%) Grade 3 (%) ## Grade 4 (%) All Grades (%) Grade 3 (%) Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis < Rash maculo-papular < Dry skin < Actinic keratosis Rash papular 5 <1 - < Erythema Palmar-plantar erythrodysaesthesia syndrome 9 < Skin lesion Musculoskeletal and connective tissue disorders Arthralgia Myalgia <1 - Pain in extremity 21 < Musculoskeletal pain 12 <1-4 < Back pain 13 <1-7 <1-11 <1 - Arthritis 4 < General disorders and administration site conditions Fatigue Edema peripheral 20 < Grade 4 (%) Page 13 of 43

14 ADRs All Grades (%) Phase III Study: Treatment Naïve Patients** Phase II Study: Patients who Failed at Least One Prior Systemic Therapy ZELBORAF Dacarbazine ZELBORAF n= n= n= 132 Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) ## Grade 4 (%) All Grades (%) Grade 3 (%) Pyrexia 21 <1-10 < Asthenia 14 <1 10 <1 2 - Gastrointestinal disorders Nausea Diarrhea <1-32 <1 - Vomiting Constipation 14 < Abdominal pain < Abdominal pain, upper 10 < Nervous system disorders Headache Dysgeusia Neuropathy peripheral < <1 - Dizziness 11 < Neoplasms benign, malignant and unspecified (incl cysts and polyps) Skin papilloma 28 <1 - < SCC of skin # <1 < Seborrhoeic keratosis 13 < Melanocytic naevus Investigations Grade 4 (%) Gammaglutamyltransferase increased 7 4 < Weight decreased <1 Metabolism and nutrition disorders Decreased appetite 22 <1-8 < Respiratory, thoracic and mediastinal disorders Cough < Page 14 of 43

15 ADRs All Grades (%) Phase III Study: Treatment Naïve Patients** Phase II Study: Patients who Failed at Least One Prior Systemic Therapy ZELBORAF Dacarbazine ZELBORAF n= n= n= 132 Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) ## Grade 4 (%) All Grades (%) Grade 3 (%) Oropharyngeal pain Dyspnoea < Injury, poisoning and procedural complications Sunburn 15 < Psychiatric disorders Depression 5 < <1 - Insomnia Renal and Urinary Disorders Acute kidney injury 10 ## 1 <1 1.4 < Grade 4 (%) * Adverse drug reactions were reported using MedDRA and graded using NCI-CTCAE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. # cuscc includes cases of keratoacanthoma and Bowen s disease. All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators (however one investigator in each of the Phase III and Phase II studies did not agree with this approach) and no dose modification or interruption was required. + Represents Safety Population, patients randomized and received at least one dose of ZELBORAF or dacarbazine. ** Data from Updated Safety Analysis with data cut-off date of February 1, ## For dacarbazine patients who crossed over to ZELBORAF only AEs with an onset date before date of crossover are included. ## Includes acute kidney injury, renal impairment, and laboratory changes consistent with acute kidney injury based on n=419 which includes 84 patients that crossed over from dacarbazine as of 27 May The following clinically relevant ADRs were reported in < 10% of the patients treated with ZELBORAF in the Phase III and Phase II studies: Skin and Subcutaneous Tissue Disorders: keratosis pilaris (9%), erythema nodosum a form of panniculitis (2%), Stevens-Johnson syndrome (<1%), toxic epidermal necrolysis (TEN) (<1%) Cardiac Disorders: atrial fibrillation (3%), cardiac failure (< 1%) Musculoskeletal and Connective Tissue Disorders: joint swelling (5%), muscle weakness (4%), Dupuytren's contracture (1%) Nervous system Disorders: VII th nerve paralysis (1%), syncope/loss of consciousness (1%) Neoplasms Benign, Malignant and Unspecified (includes cysts and polyps): basal cell carcinoma (3%) Infections and Infestations: folliculitis (8%) Eye Disorders: retinal vein occlusion (<1%), uveitis/iritis (3%) Page 15 of 43

16 Vascular Disorders: hypertension (3%), vasculitis (1%) Metabolism and Nutrition Disorders: hypokalemia (5%), dehydration (3%), tumour lysis syndrome (<1%) Gastrointestinal Disorders: pancreatitis (<1%) Investigations: blood creatinine increased (7%), electrocardiogram QT prolonged (3%) Table 2 summarizes clinically significant AEs [serious adverse events (SAEs) or grade 3 events] that occurred more frequently in females than in males in the vemurafenib arm of the Phase III trial. Females experienced approximately twice as many clinically significant events of arthralgia, photosensitivity reactions and rash compared to males in this study. Table 2 Summary of NCI CTCAE Grade 3 and SAEs in Males and Females* Body system/adverse event Grade 3: Female vemurafenib N=137 No. (% ) Serious: Female vemurafenib N=137 No. (% ) Grade 3: Male vemurafenib N=199 No. (% ) Serious: Male vemurafenib N=199 No. (% ) Skin and subcutaneous tissue disorders 35 (26) 2 (1) 26 (13) 2 (1) Rash 17 (12) 1 (<1) 11 (6) 1 (<1) Photosensitivity reaction 5 (4) -- 4 (2) -- Rash maculo-papular 4 (3) -- 4 (2) -- Pruritus 3 (2) -- 2 (1) 1 (<1) General disorders and administration site conditions 10 (7) 4 (3) 10 (5) 6 (3) Fatigue 3 (2) 1 (<1) 3 (2) 2 (1) Gastrointestinal disorder 9 (7) 2 (1) 10 (5) 5 (3) Nausea 3 (2) -- 1 (<1) -- Musculoskeletal and connective tissue disorders 10 (7) 3 (2) 9 (5) 3 (2) Arthralgia 7 (5) 1 (<1) 4 (2) 1 (<1) Respiratory, thoracic and mediastinal disorders 5 (4) 2 (1) 5 (3) 1 (<1) Pulmonary embolism 2 (1) 2 (1) 1 (<1) -- * Data cut-off date December 30, 2010 Abnormal Hematologic and Clinical Chemistry Findings Liver laboratory abnormalities in the Phase III clinical study are summarised below (Table 3) as the proportion of patients who experienced a shift from baseline to grade 3 or 4. Page 16 of 43

17 Table 3 Change from Baseline to Grade 3/4 Liver Enzyme Abnormalities** Change from baseline to grade 3/4 Parameter ZELBORAF (% ) Dacarbazine (% ) GGT AST ALT* Alkaline phosphatase* Bilirubin* *For ALT, Alkaline Phosphatase and Bilirubin there were no patients with a change to grade 4 in either treatment arm. **Data cut-off date December 30, 2010 Creatinine changes from baseline in the Phase III clinical study are summarized below (Table 4) as the proportion of patients who experienced a shift from baseline. Table 4 Creatinine change from baseline * Change >= 1 grade from baseline (all grade) ZELBORAF (% ) Dacarbazine (% ) Change >= 1 grade from baseline to grade 3 or higher To grade To grade *Data cut-off date June 25, 2013 Clinical Trial Adverse Drug Reactions (Phase II Study in Patients with Brain Metastases) In a phase II study in 146 patients with BRAF V600 mutation-positive melanoma metastatic to the brain, the most common adverse drug reactions (> 20% all grades) reported were: arthralgia, rash, hyperkeratosis, photosensitivity reaction, fatigue, alopecia and QT prolongation, the majority of which were mild or moderate in intensity. Post-Market Adverse Drug Reactions Events included in this section have been identified post-approval, which includes spontaneous case reports as well as adverse events from ongoing or completed clinical studies. Page 17 of 43

18 Table 5 Adverse Drug Reactions Reported in the Post Marketing Setting System organ class (SOC) ADR Hepatobiliary disorders Blood and lymphatic systems disorders Neoplasms benign, malignant and unspecified (including cysts and polyps) Liver injury, including cases reported as hepatic failure Neutropenia, including cases of febrile neutropenia Chronic myelomonocytic leukemia (CMML) * Pancreatic adenocarcinoma # Immune system disorders Skin and subcutaneous tissue disorders Injury, poisoning and procedural complications Drug reaction with eosinophilia and systemic symptoms (DRESS) Panniculitis Radiation sensitization and radiation recall^ Gastrointestinal disorders Renal and urinary disorders Musculoskeletal and connective tissue disorders Pancreatitis Acute kidney Injury Plantar fascial fibromatosis *Progression of pre-existing chronic myelomonocytic leukemia with N-RAS mutation # Progression of pre-existing pancreatic adenocarcinoma with k-ras mutation ^ Includes recall phenomenon, radiation skin injury, radiation pneumonitis, radiation esophagitis, radiation proctitis, radiation hepatitis, cystitis radiation, and radiation necrosis. Neoplasms benign, malignant and unspecified (including cysts and polyps): One case of progression of N-RAS mutated CMML occurred in a male patient with metastatic melanoma treated with ZELBORAF for less than two weeks. The patient had an elevated white blood cell count prior to starting ZELBORAF treatment, which was consistent with the pre-existence of a clinically undiagnosed N-RAS mutant CMML. After the first dose of ZELBORAF, laboratory results showed a marked leucocytosis and monocytosis and ZELBORAF treatment was subsequently held. There was a temporal relationship between ZELBORAF treatment and increase in white blood cell (WBC) and absolute monocyte counts, through multiple cycles of dechallenge and rechallenge. Hepatobiliary disorders: Two cases reported as hepatic failure occurred following treatment with ZELBORAF monotherapy. Elevations in ALT of 15x and 58x ULN 1 together with elevations in bilirubin of 5x and 2.5x ULN, respectively, occurred within 2 months of starting treatment. Alkaline phosphatase levels were normal in one patient and not reported in the other. Both patients recovered fully following permanent discontinuation of ZELBORAF. 1 ULN: Upper Limit of Normal Page 18 of 43

19 Other cases of drug-induced liver injury defined as any one of the following: a) 5x ULN ALT, b) 2x ULN ALP or c) 3x ULN ALT and simultaneous 2x ULN bilirubin, were also reported in the post-market setting in patients treated with ZELBORAF. Median time to onset was 44 days after the initial dose. Skin and subcutaneous tissue disorders: Panniculitis, a painful inflammation of subcutaneous fat cells or surrounding connective tissues, has been reported in patients receiving ZELBORAFmonotherapy; the majority of whom were women. Renal and Urinary Disorders: A broad spectrum of renal adverse drug reaction cases has been reported with ZELBORAF ranging from mild to moderate creatinine elevations to acute interstitial nephritis and acute tubular necrosis. In most cases, creatinine elevations appeared to be reversible in nature. DRUG INTERACTIONS Overview A single drug-drug interaction study involving multiple doses of vemurafenib (960 mg twice daily) followed by a cocktail of single dose of substrates for CYP2C19, CYP2D6, CYP2C9, CYP1A2 and CYP3A4 was conducted in melanoma patients. Interactions were observed between vemurafenib and substrates for CYP1A2, CYP2D6, CYP2C9 and CYP3A4 (see Drug- Drug Interactions below). No interactions were observed with the CYP2C19 substrate. Vemurafenib causes QTc prolongation (see WARNINGS AND PRECAUTIONS, Cardiovascular). The concomitant use of vemurafenib with anti-arrhythmic medicines and other QTc-prolonging drugs should be avoided to the extent possible. These findings are discussed further below. Drug-Drug Interactions Effects of Vemurafenib on CYP Substrates CYP1A2 inhibition was observed when a single dose of caffeine was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 2.6-fold increase (maximum up to 5-fold) in caffeine plasma exposure (AUC last ) after vemurafenib treatment. In a clinical trial with tizanidine (a sensitive CYP1A2 substrate), administration of multiple oral doses of vemurafenib (960 mg twice daily) to 18 BRAF V600 mutation-positive cancer patients for 20 days, significantly increased the exposure (AUC last and C max ) of a single 2 mg oral dose of tizanidine by approximately 4.2-fold and 2.2-fold, respectively. Concomitant use of vemurafenib with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended. If co-administration can not be avoided, toxicities should be monitored closely and a dose reduction of concomitant CYP1A2 substrates should be considered. Page 19 of 43

20 In another clinical trial, CYP3A4 induction was observed when a single dose of midazolam was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 39% decrease (maximum up to 80%) in midazolam plasma exposure (AUC last ) after vemurafenib treatment. CYP2D6 inhibition was observed when a single dose of dextromethorphan was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 47% increase (maximum up to 264%) in dextromethorphan plasma exposure (AUC last ) after vemurafenib treatment. When a single dose of warfarin (CYP2C9 substrate) was co-administered after repeat dosing with vemurafenib for 15 days, a reduced clearance resulting in a 5-hour longer terminal half-life and a mean increase of 23% (90% CI: 1.15, 1.31) in S-warfarin plasma exposure (AUC inf ) was observed. Additional studies demonstrated that vemurafenib inhibited CYP2C9 in vitro (see TOXICOLOGY). Therefore caution should be exercised and additional INR (international normalized ratio) monitoring should be considered when vemurafenib is co-administered with warfarin in patients. Vemurafenib may increase the plasma exposure of drugs predominantly metabolized by CYP1A2, CYP2C9 and CYP2D6 and decrease the plasma exposure of drugs predominantly metabolized by CYP3A4. Dose reductions for medications predominantly metabolized via CYP1A2 and CYP2D6 should be considered based on their therapeutic windows before concomitantly treating with vemurafenib. Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be excluded. Concomitant administration of CYP2C8 substrates with a narrow therapeutic window should be made with caution since vemurafenib may increase their concentrations. Effects of Concomitant Medications on Vemurafenib Preclinical studies suggest that CYP3A4 metabolism and glucuronidation are responsible for the low level of metabolism of vemurafenib. In a clinical study, co-administration of rifampin, a strong CYP3A4 inducer, significantly decreased the plasma exposure of vemurafenib (AUC) by approximately 40% following a single 960 mg dose of vemurafenib (see ACTION AND CLINICAL PHARMACOLOGY- Metabolism). There are no clinical data available showing the effect of other strong inducers (e.g., phenytoin, carbamazepine, rifabutin, phenobarbital) or inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, saquinavir, ritonavir, indinavir, nelfinavir, voriconazole) of CYP3A4 activity on vemurafenib exposure. Caution is advised in co-administering these drugs to avoid altering exposure to vemurafenib. Page 20 of 43

21 Interaction of Vemurafenib with Drug Transport Systems In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor of efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). A clinical drug interaction study using a P-gp substrate drug (Digoxin) demonstrated that multiple oral doses of vemurafenib (960 mg twice daily) increased the exposure of a single oral dose of digoxin, with an approximately 1.8 and 1.5 fold increase in digoxin AUC last and C max, respectively. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates. Dose reduction of the concomitant P-gp substrate drug may be considered, if clinically indicated. The effects of vemurafenib on drugs that are substrates of BCRP, and the effects of BCRP inducers and inhibitors on vemurafenib exposure are unknown. Caution is advised in coadministering vemurafenib with these drugs to avoid suboptimal concentrations of vemurafenib and/or of the concomitant medications. In vitro studies have also demonstrated that vemurafenib is an inhibitor of bile salt export pump (BSEP). Although the in vivo relevance of this finding is unknown, a possible role of BSEP inhibition as an underlying cause of liver injury in humans cannot completely be ruled out. Radiation Sensitization and Radiation Recall Radiation sensitization and radiation recall has been reported in patients receiving vemurafenib (see WARNINGS AND PRECAUTIONS and Post Market Adverse Drug Reactions). In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens). Radiation sensitization and radiation recall has been reported in targeted tissues in association with both concurrent and non-concurrent use of ZELBORAF. Toxicity in this setting has manifested as both cutaneous and non-cutaneous (e.g. pneumonitis, esophagitis, cystitis, brain and liver toxicity) injury. QTc Prolonging Drugs Drugs that have been associated with QTc interval prolongation and/or torsade de pointes should not be administered with vemurafenib if possible. These include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc prolongation and/or torsade de pointes: Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide, dronedarone) Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide) Class IC antiarrhythmics (e.g., flecainide, propafenone) antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone) antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants [e.g., amitriptyline, imipramine, maprotiline]) opioids (e.g., methadone) Page 21 of 43

22 macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus) quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin) pentamidine antimalarials (e.g., quinine, chloroquine) azole antifungals (e.g., ketoconazole, fluconazole, voriconazole) domperidone 5-hydroxytryptamine (5-HT)3 receptor antagonists (e.g., dolasetron, ondansetron) prochlorperazine tyrosine kinase inhibitors (e.g., sunitinib, lapatinib) histone deacetylase inhibitors (e.g., vorinostat) beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol) Drug-Food Interactions Grapefruit, grapefruit juice and other foods that are known to affect CYP3A4 and P-gp activity should be avoided during treatment with vemurafenib. Drug Herb Interactions Interactions with herbal products have not been established. St. John s wort (Hypericum perforatum) is an inducer of CYP3A4 that may increase the metabolism of vemurafenib and decrease vemurafenib blood levels. Drug Laboratory Test Interactions Interactions between ZELBORAF and laboratory tests have not been studied. Drug-Lifestyle Interactions No studies on the effects of ZELBORAF on the ability to drive or operate machinery have been performed. Fatigue and vision problems have been reported and patients taking ZELBORAF should observe caution when driving or operating machines. DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment Recommended Dose The recommended dose of ZELBORAF (vemurafenib) is 960 mg (four 240 mg tablets) twice daily. It is recommended that treatment with ZELBORAF continue until disease progression or the development of unacceptable toxicity (see Table 6). Page 22 of 43

23 Dose Adjustment Management of adverse events may require dose reduction, temporary interruption or treatment discontinuation of ZELBORAF (Table 6). Initiation of treatment with ZELBORAF is not recommended in patients with QTc>500 ms. If, during treatment, the QTc exceeds 500 ms (CTCAE grade 3), ZELBORAF treatment should be temporarily interrupted. Re-initiation of treatment should occur once the QTc decreases below 500 ms and at a lower dose (Table 7 below). Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc meets values of both > 500 ms and > 60 ms increase from pre-treatment values and if recommended dose reductions are not effective to manage when the QTc meets values of > 500 ms but 60 ms increase from pre-treatment values (Table 7). Dose modifications or interruptions are not recommended for cutaneous squamous cell carcinoma (cuscc). Dose reductions resulting in a dose below 480 mg twice daily are not recommended. Table 6 Dose Adjustments Toxicity Grade (CTC-AE)* Grade 1 or tolerable Grade 2 Intolerable Grade 2 or Grade 3 Grade 4 Recommended Vemurafenib Dose Modification Vemurafenib dose changes during current treatment period No change Dose modification at resumption of treatment 1st Appearance^ Interrupt until resolved: grade 0 1 Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose has already been lowered) 2 nd Appearance^ 3 rd Appearance^ 1 st Appearance^ 2 nd Appearance^ Interrupt until resolved: grade 0 1 Discontinue permanently Discontinue permanently or interrupt until resolved: grade 0 1 Discontinue permanently N/A Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily) N/A Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily) *The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE) ^ Any AE where treatment interruption and dose reduction are clinically indicated and undertaken N/A Page 23 of 43

24 Table 7 Dose Modification Schedule Based on Prolongation of the QTc Interval QTc interval and QTc value from pre-treatment Recommended dose modification QTc>500 ms at baseline QTc >500 ms during treatment and change from pre-treatment values >60 ms QTc>500 ms during treatment and change from pre-treatment value remains 60 ms Treatment not recommended. Discontinue permanently. 1 st occurrence Temporarily interrupt treatment until QTc decreases below 500 ms. Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose has already been lowered). 2 nd occurrence Temporarily interrupt treatment until QTc decreases below 500 ms. Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily). 3 rd occurrence Discontinue permanently. Hepatic impairment Based on population pharmacokinetic analysis, no adjustment to the starting dose is needed for patients with pre-existing mild (total bilirubin > x ULN) or moderate (total bilirubin >1.5-3x ULN) hepatic impairment. ZELBORAF in patients with severe hepatic impairment has not been studied and therefore, safety, efficacy and potential need for dose adjustment are unknown. Administration The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 hours later. Both doses should be taken consistently with or without food to maintain an effective therapeutic dose as the impact of food on ZELBORAF exposure is not known. ZELBORAF tablets should be swallowed whole with a glass of water. ZELBORAF tablets should not be chewed or crushed. Missed Dose If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time. Vomiting In case of vomiting, continue to take ZELBORAF as usual and do not take an additional dose. Page 24 of 43